Efficacy, as assessed by time to Grade 2 or less in the West Haven criteria sustaining for 4 hours or longer [ Time Frame: Time to Grade 2 or less sustaining for 4 hours or longer ] [ Designated as safety issue: No ]

Efficacy, as assessed by proportion of assessments with a 2-grade improvement, using West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]

Efficacy, as assessed by proportion of assessments with 1-grade improvement, using West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]

Efficacy, as assessed by time spent in an improved state by 1 or 2 grades using the West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]

Efficacy, as assessed by percentage of subjects with a 1 or 2 grade improvement, using the West Haven criteria [ Time Frame: At any time point and at each specific time point ] [ Designated as safety issue: No ]

Efficacy, as assessed by severity of hepatic encephalopathy using the Glasgow Coma Scale [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]

5.5 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours)

Other Name: Ammonul®

Experimental: 2

Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%

2.75 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours)

Other Name: Ammonul®

Placebo Comparator: 3

Drug: placebo solution (10% dextrose)

Placebo solution (10% dextrose), IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours)

Detailed Description:

Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome seen in patients with liver disease. The pathogenesis of HE is incompletely understood, but several pieces of evidence identify ammonia as a key factor in the development of HE. The liver normally detoxifies ammonia produced in the gastrointestinal tract. However, in patients with cirrhosis, portosystemic shunting allows ammonia to bypass the liver and reach the systemic circulation and the brain. The accumulation of ammonia in the brain, through mechanisms not yet fully defined, lead to changes of consciousness, intellectual function, and behavior.

Ammonul is currently approved as adjuvant therapy for the management of hyperammonemia and associated encephalopathy in patients with deficiencies in the enzymes of the urea cycle. Ammonul removes nitrogenous ammonia in these patients through pathways alternative to the urea cycle. It is anticipated that in patients with HE, Ammonul may lead to the scavenging of ammonia through these alternative biochemical pathways taking place in tissues other than the liver.

This study is designed to test the efficacy and safety of IV Ammonul® as a treatment for acute episodes of elevated ammonia in patients with Grade 3 or 4 HE.

Eligibility

Ages Eligible for Study:

18 Years to 75 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Male or female between the ages of 18 and 75 years

Signed written informed consent by subject's representative

Current diagnosis of chronic liver disease with cirrhosis

West Haven score of Grade 3 or 4 Hepatic Encephalopathy

Weight between 45 and 150 kg

Elevated venous ammonia concentration, defined as a value above the normal range at the local laboratory

Use of probenecid, valproate, penicillin or its derivatives, or corticosteroids (oral or IV) within the last 24 hours

Use of any sedatives, benzodiazepines, or any neuro- or psycho-active drugs in the last 6 hours and a positive urinary drug screen

Subjects who received any mind-altering agents (such as barbiturates, propofol, opioids, or benzodiazepines) to assist with intubation are not eligible while the effects of the drug are still apparent

Congestive heart failure (New York Heart Association Class III or IV)

Seizures, dementia, or any neurologic or psychiatric condition within the last 72 hours that may interfere with the assessment of the mental state

Current diagnosis of major aspiration pneumonia or pulmonary edema accompanied by an oxygen saturation of ≤ 90% while breathing supplemental oxygen

Laboratory test abnormalities determined to be clinically significant by the investigator

Enrollment in another experimental (interventional) protocol within the last 30 days or 5 half-lives of the experimental drug, whichever s longer

Any medical condition, which in the opinion of the investigator would constitute a contraindication to enrollment in the study

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00597909